Mildly oxidized LDL induces activation of platelet-derived growth factor β-receptor pathway

Background-Mildly oxidized LDL (moxLDL) is thought to play a role in atherogenesis. MoxLDL induces derivatization of cell proteins and triggers a variety of intracellular signaling. We aimed to investigate whether moxLDL-induced protein derivatization may influence the activity of platelet-derived growth factor receptor beta (PDGFR beta), a tyrosine kinase receptor of major importance in vascular biology and atherogenesis. Methods and Results-In cultured rabbit arterial smooth muscle cells, moxLDL induces activation of the PDGFR beta signaling pathway, as shown by PDGFR beta tyrosine phosphorylation on Western blot and coimmunoprecipitation of SH2-containing proteins. The cellular events involved in the moxLDL-induced PDGFR beta activation can be summarized as follows. Oxidized lipids from moxLDL trigger two phases of PDGFR beta activation involving two separate mechanisms, as shown by experiments on cultured cells (in situ) and on immunopurified PDGFR beta (in vitro): (1) the first phase may be mediated by 4-hydroxynonenal, which induces PDGFR beta adduct formation and subsequent PDGFR beta activation (antioxidant-insensitive step); (2) the second phase involves ceramide-mediated generation of H2O2 (these steps being inhibited by tosylphenylalanylchloromethylketone, an inhibitor of ceramide formation, and by antioxidant BHT, exogenous catalase, or overexpressed human catalase). Because 4-hydroxynonenal-PDGFR beta adducts are also detected in atherosclerotic aortas, it is suggested that this novel mechanism of moxLDL-induced PDGFR beta activation may occur during atherogenesis. Conclusions-MoxLDL acts as a local autoparacrine mediator in the vascular wall, and PDGFR beta acts as a sensor for both oxidized lipids and oxidative stress. This constitutes a novel mechanism of PDGFR beta activation in atherosclerotic areas.